The thyroid hormone tetraiodothyronine or thyroxine (T4) is secreted by the follicular cells of the thyroid gland in response to the pituitary-gland hormone TSH, the production of which is regulated in turn by the hypothalamic hormone TRH. The pituitary gland also secretes the T3 hormone (triiodothyronine or liothyronine). In fact, most of the T3 in the body results from conversion of T4 to T3 outside the thyroid gland. T3 is 4-5 times more potent that T4, which means that one mg of T3 has a much greater effect on the body than one mg of T4.
The secretion of thyroid hormones follows a circadian rhythm. The highest levels of T3 and T4 are reached during the night and the early hours of the morning.
T3 and T4 are essential for the normal body growth of children and for the maturation of the various body systems, especially the skeleton, and regulate metabolic activity in adults, influencing the function of every organ and tissue. In particular, T3 and T4 increase oxygen consumption at rest, raising the basal metabolism, the body temperature and the daily calories requirement. They regulate carbohydrate metabolism, promoting glycogenolysis and gluconeogenesis, and increase the activity of the enzymes involved in glucose oxidation. Thyroid hormones are involved in lipolysis and lipogenesis, regulate protein synthesis, exercising a trophic effect on the muscle, and affect the cardiovascular system.
Thyroid hormones are essential to the cardiac function: they increase myocardial contractility (positive inotropic effect), increase the heart rate (positive chronotropic effect) and increase venous return to the heart.
In general, the effect of thyroid hormones is mainly anabolic at low doses, whereas they have a catabolic action at high doses. In situations of physiological deficiency of thyroid hormones, as in the case of primary and secondary hypothyroidism, a treatment based on thyroid hormones is required, administered as such or in the form of sodium salts or hydrates. The treatment continues throughout the patient's life, and the posology (dose and frequency of administration) is customized according to the patient's response.
Selecting the dose is a critical aspect of thyroid hormone treatments: an under-dose leads to a poor response, while an excessive dose can produce toxic symptoms of hyperthyroidism such as tachycardia, sweating, weight loss, nervousness, diarrhea, bone resorption due to activation of the osteoclasts, and heart problems. It is therefore important for patients to be able to count on reliable formulations in terms of dose accuracy.
T4 and T3 hormones are conveniently administered via the oral route. Although T4 and T3 hormones are both therapeutically effective, the administration of T4 is generally preferred since T3 is too rapidly absorbed from the intestine and this rapid absorption may cause thyroid hormone toxicity (hyperthyroidism). Mixtures of T3 and T4 are also not preferred because the two hormones have different pharmacokinetic and potency, which complicates the establishment of a suitable dosage regime for the patient.
T4 hormone is conveniently administered in the form of a solution, which allows a more precise dosing as compared to solid forms. The administration of T4 solutions presents nevertheless some challenges: in fact, T4 solutions are reported to prematurely convert in part to T3 during storage. The extent of conversion is difficult to predict, since the conversion rate may be affected by a variety of environmental conditions. As a consequence, at the time of administration, T4 solutions may be contaminated with non-predictable, sometimes significant levels of T3. This causes inaccuracy of the hormone dose actually administered, with risk of overdosage due to the higher potency of T3. Due to the quite higher potency of T3 vs. T4, even a small amount of formed T3 may significantly increase the overall dosage of administered hormone, with potential consequences for the patient caused by over-dosing.
A further difficulty derives from the low water solubility of thyroid hormones, causing them to partly precipitate from solutions during storage and/or in consequence of temperature changes. A partial improvement in this area is reported in WO2010/086030, where the thyroid hormones are formulated in water-alcohol-glycerol solutions showing a good stability. The stability was further enhanced by packaging the solution within containers made of specific polymers. In an attempt to further increase stability, other packaging solutions are described in WO2013072304, wherein the water-alcohol-glycerol solution was double-packaged (i.e. contained in a plastic container which is contained in a sachet), or single-packaged in an improved multilayered plastic container. Nevertheless, under these conditions, a significant degree of instability was observed as regards to conversion of T4 into T3.